The coronary heart disease (CHD) of postmenopausal women likely begins premenopausally and is exacerbated by estrogen deficiency. Thus, soy protein isolate with isoflavones (SOY), which is often consumed postmenopausally as a "heart healthy" supplement, may also offer premenopausal cardiovascular benefit. Yet, the optimal timing for intervention (in relation to menopausal status and lesion stage) remains uncertain, as does the extent of cardiovascular protection provided to women first exposed to SOY as adults. Premenopausal monkeys (Macaca fascicu/aris) are a surrogate for reproductive aged women in the study of atherosclerosis and CHD risk. In this model, the stress of social subordination (low status) induces estrogen deficiency, accelerates atherogenesis, and impairs vascular responsivity. Treatment of low status premenopausal females with exogenous estrogen reduces the extent of postmenopausal atherosclerosis independent of postmenopausal hormone exposure, demonstrating the potential benefit of premenopausal prevention. It is therefore proposed to expand the scope of an ongoing study that currently contains sociallyhoused, premenopausal monkeys consuming a moderately atherogenic diet, in which protein is derived from either SOY or casein-lactalbumin (C/L). This study was designed initially to determine whether SOY inhibits premenopausal coronary atherosclerosis in stressed individuals and whether such effects are influenced by endogenous estrogen. This design does not permit determination of the relative postmenopausal cardiovascular effects of pre- vs. postmenopausal SOY exposure, a comparison that could directly inform the treatment of postmenopausal women. The present application proposes to answer the odginai premenopausal study question by assessing atherosclerosis in an lilac artery biopsy (a validated coronary artery surrogate), eliminating the need to necropsy the premenopausal animals. Instead, the study will be extended to include a surgically postmenopausal phase which, by switching the protein source for half of the monkeys, will cross pre- and postmenopausal exposure to C/L and SOY in a 2 x 2 factorial design encompassing 4 treatment conditions (SOY ? SOY, SOY ? C/L, C/L ? SOY, and C/L ? C/L). The study will terminate with the evaluation of lilac, coronary, and carotid artery atherosclerosis. The aims are to test the hypothesis that the timing of SOY supplementation (pre- or postmenopausal) affects postmenopausal plaque progression and complications, and to determine the impact of chronic SOY exposure on noncardiovascutar, health-related outcomes.